This laboratory has long been interested in the role of enterically derived endotoxin in the initiation and perpetuation of liver injury, mechanisms involved in the process, and the effect of modifying endotoxicity on the extent of experimental hepatic damage. Work in this area has been hampered in the past by the lack of an endotoxin marker that could be used to quantitate endotoxemia. Our laboratory has developed an immunoradiometric assay (IRMA) for E. coli 026 that presently detects the specific LPS at a concentration as low as 10 ng./ml. The appearance, and amount of E. coli 026 in the circulation arising from oral administration of the LPS will be studied in a variety of acute and chronic rat liver injuries. In addition, the same technique will be used to develop an assay for lipid A, a shared endotoxin core in the hope of detecting heterologous endotoxins in the circulation. As an extension of work completed, we propose to further investigate our initial observations on the kinetics of endotoxin absorption in the everted gut sac of normal rats, and to study also, absorption in sacs from rats with acute and chronic liver injury. Using this model, the role of bile salts, pancreatic enzymes, pH and histamine in the absorption and detoxification of endotoxin will also be studied. On the basis of completed studies, we feel that endotoxemia of enteric origin may be important in acute renal failure (ARF) associated with shock, trauma, or sepsis. We propose extending these studies in glycerol-induced renal failure to detection of E. coli 026 LPS by the IRMA technique, to the study of blood flow to the gut and kidneys by the labeled microsphere technique and to the effect of tolerance on the renin-angiotensin axis and renal prostaglandin synthesis. Studies on the modification of endotoxicity will also be done testing methods of immunization, drug modification and charcoal hemoperfusion.